Research in this lab is biological question driven. This means that we would not be limited by technique hurdles, instead we use an array of different methods, such as x-ray crystallography, mass spectrometry, cryo-EM, SAXS, high-throughput screening, deep sequencing, in vitro & in vivo evaluation etc., to investigate biological questions with clinical significance. Training in this lab entails scientific curiosity and persistence, encourages critical thinking and cooperation, while it also offers a free climate of interdisciplinary research and a chance to master difference techniques.
We study the molecular basis of a range of high-risk infectious diseases and genetic diseases, so as to identify novel therapeutic vulnerabilities in organisms. On top of these basic research, we seek to translate gained knowledge into the development of preventive opportunities like vaccine immunogens, and therapeutic interventions such as gene therapies.
Examples of our recent research are briefed below:
1. 1. Env proteins are the focus of HIV-1 vaccine development. We investigated the structures and immune recognition of the Envs from Asia prevalent HIV-1 subtypes (i.e., CRF01_AE and CRF07_BC), revealed the unique features of their V1 regions, associated them with certain bNAbs resistance, and unraveled the epitope and unique dual mechanism of a bNAb from CRF01_AE infected individuals (Nat. Commun., 2023). These findings broaden our understanding of Asia prevalent HIV-1 subtypes and shed lights on future immunofocusing HIV-1 vaccine design.
2. 2. Though applying structure-guided protein engineering, we contributed in the development of several high-precision gene editing tools (Cell Res., 2017; Nat. Biotechnol., 2018a; Nat. Biotechnol., 2018b; Cell Rep., 2020；Nat. Cell Biol., 2021; Nat. Commun., 2022). We are now actively exploring the application potential of these gene editing tools in genetic diseases and high-risk infectious diseases. Recently, we have demonstrated that when combined with structure-guided editing sites selection, high-precision genome editing tools like Prime Editor (PE) could accurately ablate the virus-related roles of host factors to provide long-lasting, broad-spectrum antiviral effects while leaving their physiological functions unaffected (Medcomm, 2023).
3. By performing detailed and comparative analysis on the fusion core structures of α-and β-human coronaviruses (HCoVs), we revealed the commons and differences among the HR1s from different HCoVs (Acta Cryst. D., 2018). Built upon the knowledge gained and collaborating with a team of virologists from Fudan University, we then successfully developed a pan-coronavirus (pan-CoV) inhibitor EK1, which blocks the host entry process of multiple HCoVs in vitro & in vivo by functioning as a HR2 mimicry targeting their HR1s (Sci. Adv., 2019). Most recently, we further unraveled the antigenic landscape of α-HCoV spike protein to provide clues for the development of broadly effective CoV vaccines (Commun. Biol., 2022).
4. 4. 3C protein is one of the drug development focuses of Enterovirus, yet its hydrophilic protease active center has frustrated previous drug discovery efforts. Using an integrative approach which combines mass spectrometry and x-ray crystallography, we identified unique sites of therapeutic vulnerability on 3C and demonstrated that 3C plays an important regulatory role in enteroviruses genome replication and that this unexplored role could serve as a novel antiviral intervention opportunity against enterovirus infections (Proc. Natl. Acad. Sci. U.S.A., 2020). We are now screening for compounds against this newly discovered target site.
